Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (
            Hyp
            ) mouse model

Abstract Context: Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25 dihydroxyvitamin vitamin D concentrations and ectopic and vascular calcifications. Recessive loss-of-function mutations in UDP-N-acetyl-α-d-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC. Objective: The objective of the study was to determine the relationship between GALNT3 and FGF23 in familial TC. Design, Setting, and Patients: We assessed the major biochemical defects and potential genes involved in patients with TC. Intervention: Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide. Results: We report a patient homozygous for a GALNT3 exon 1 deletion, which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein has been identified as a possible regulator of phosphate homeostasis. Serum matrix extracellular phosphoglycoprotein levels, however, were normal in the family with GALNT3-TC and a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved after combination therapy. Conclusions: Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may be effective for reducing the tumoral burden associated with familial TC.

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Abstract P058: Serum Fibroblast Growth Factor-23 Does Not Have a Linear Relation to Cardiovascular Mortality

Circulation ◽

10.1161/circ.131.suppl_1.p058 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Karl Krupp ◽

Emir Veledar ◽

Purnima Madhivanan ◽

Robert Cook ◽

Khurram Nasir

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Cardiovascular Mortality ◽

Meta Analysis ◽

Fibroblast Growth Factor 23 ◽

High Serum ◽

P Value ◽

Fibroblast Growth ◽

Significant Difference ◽

Cvd Mortality

Introduction: Fibroblast Growth Factor 23 (FGF23) is bone-derived hormone regulating phosphate homeostasis as part of a newly described bone-kidney axis. Several studies have demonstrated that elevated circulating FGF23 levels are independently associated with cardiovascular mortality. Methods: A systematic review was conducted according to Meta-analysis of Observational Studies in Epidemiology Group guidelines. Six databases (PubMed-Central, Ovid-MEDLINE, EMBASE, Web of Science, BIOSIS and Cochrane Database of Systematic Reviews) were searched for articles published between 2000 and 2014 examining the longitudinal association between FGF23 and CVD mortality among populations without prior CVD, Chronic Kidney Disease, or Diabetes. The review yielded 1,961 articles, of which 982 met the inclusion criteria. About 893 abstracts were excluded during the title and abstract screen, and an additional 92 after full text review. Only three articles met the review criteria and were included in the meta-analysis. Data from selected articles were abstracted and independently assessed for quality by two reviewers. Summary estimates and associated 95% confidence intervals were included in fixed and random-effects models. The presence of heterogeneity was evaluated using a Q-statistic with a conservative p-value of 0.10. All analyses were performed using R library meta. Results: Data for 15,379 participants were included in the meta-analysis. The hazard ratio for quartiles two and four when compared with quartile one,the reference category, were 1.29 (1.06- 1.58; p=0.01) and 1.31 (1.077-1.59; p=0.0068) respectively. There was no significant difference in CVD mortality between the third and first quartile. There was also no evidence of heterogeneity observed (I2 = 0%, p = 0.611). Conclusions: This study found a U-shaped association between FGF23 and CVD mortality suggesting that either low or high serum levels increase risk for CVD mortality. Current strategies focus on lowering high levels of circulating FGF23, but little attention has been given to understanding optimal levels necessary to prevent CVD mortality. If this U-shaped relationship between FGF23 and CVD mortality is real, the possible links, causes, and mechanisms require additional research.

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Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease

Kidney International ◽

10.1016/j.kint.2019.07.026 ◽

2019 ◽

Vol 96 (6) ◽

pp. 1346-1358 ◽

Cited By ~ 12

Author(s):

Connor Francis ◽

Guillaume Courbon ◽

Claire Gerber ◽

Samantha Neuburg ◽

Xueyan Wang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Growth Factor ◽

Kidney Disease ◽

Mouse Model ◽

Cardiac Function ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Ferric Citrate ◽

Fibroblast Growth

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Parathyroid Hormone Regulates Fibroblast Growth Factor-23 in a Mouse Model of Primary Hyperparathyroidism

Journal of the American Society of Nephrology ◽

10.1681/asn.2006070783 ◽

2007 ◽

Vol 18 (10) ◽

pp. 2683-2688 ◽

Cited By ~ 146

Author(s):

Takehisa Kawata ◽

Yasuo Imanishi ◽

Keisuke Kobayashi ◽

Takami Miki ◽

Andrew Arnold ◽

...

Keyword(s):

Parathyroid Hormone ◽

Growth Factor ◽

Mouse Model ◽

Primary Hyperparathyroidism ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Calciprotein particles and fibroblast growth factor 23 contribute to the pathophysiology of hypercalcemia in a patient with renal sarcoidosis

Clinical Kidney Journal ◽

10.1093/ckj/sfz086 ◽

2019 ◽

Author(s):

Yoshitaka Iwazu ◽

Makoto Kuro-o ◽

Yutaka Miura ◽

Shin-ichi Takeda ◽

Toshiyuki Yamada ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Oral Prednisone ◽

Laboratory Data ◽

High Serum ◽

Serum Phosphate Level ◽

Phosphate Metabolism ◽

Fibroblast Growth ◽

Calciprotein Particles

Abstract In patients with sarcoidosis, dysregulated calcium metabolism is one of the frequently observed complications. However, little attention has been paid to abnormal phosphate metabolism. Herein we present the case of a 42-year-old Japanese man with renal sarcoidosis who developed acute kidney injury due to hypercalcemia and nephrolithiasis. Laboratory data showed hypercalcemia with a normal serum phosphate level and high serum 1,25-hydroxyvitamin D3, fibroblast growth factor 23 (FGF23) and calciprotein particle (CPP) levels. After treatment with oral prednisone and bisphosphonate, the laboratory abnormalities and renal dysfunction were resolved. Thus increases in FGF23 and CPP may indicate disturbed phosphate metabolism in renal sarcoidosis.

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